Osteoarthritis (OA) is the most common form of arthritis and a major cause of activity limitation and physical disability in the elderly: 80%-90% of humans over the age of 65 suffer from OA. Available treatments for OA are mostly palliative with limited specificity. In fact, the recently identified serious side effects of some intra- oral COX-2 selective inhibitors (i.e. Vioxx, Bextra) underscore the need for the development of novel anti- inflammatory therapies for OA. The purpose of this Exploratory/Developmental R21 grant application is to develop a novel, simple and highly efficient method for the intra-articular delivery of siRNA to joints for the management of arthritis. Our model aims at significantly improving the transduction efficacy of siRNA to soft and hard tissues of joints via a non-invasive, one-time application that will result in sustainable therapeutic siRNA titers over prolonged periods of time (several months). Our strategy is based on combining the unique properties of the feline immunodeficiency viral vector (FIV) with the therapeutic properties of siRNA targeting key inflammatory genes. Specifically, our laboratory has demonstrated that VSV-G pseudo typed FIV vectors can successfully be used in stably transducing hard and soft tissues of joints in adult mice following a single intra-articular injection while evading the elicitation of an innate immune response. This method of direct intra-articular administration also confines the therapeutic effects within the joint capsule (thus minimizing any off-target side effects) following a simple, straight forward injection that can be readily performed clinically in an ambulatory setting without the need of open joint surgery or other invasive procedure. We hypothesize that FIV-mediated intra-articular delivery of siRNA constructs targeting the inducible COX-2 and/or mPGES-1 genes will ameliorate the development of joint pathology, pain and dysfunction in the Col1- IL1beta(XAT) transgenic mouse model of mono-arthritis. We have initially selected to focus on these inflammatory factors because the cyclooxygenase pathway appears to serve as a node of convergence in arthritis as supported by research studies as well as the extensive use and relative clinical success of non-steroidal anti- inflammatory drugs. Based on our strategy, we will develop FIV(siRNA) vectors for the transfer of the aforementioned siRNA constructs to joints (knee and tempromandibular joint) of adult mice suffering from arthritis. We evaluate the efficacy of these FIV(siRNA) vectors in ameliorating joint pathology, pain and dysfunction will be assessed in the Col1-IL1beta(XAT) arthritis model following intra-articular injection into the joints (knee and/or tempromandibular joint) of adult mice. Emphasis will be given in evaluating COX-2 and/or mPGES-1 expression as they are targets of our FIV(siRNA) therapy over time as well as assessing potential inflammatory responses elicited by this siRNA therapy. [unreadable] [unreadable] [unreadable]